Process for preparing simvastatin

ABSTRACT

The present invention relates to an improved process for preparing simvastatin and more particularly, the improved process for preparing simvastatin expressed by formula 1 with high yield and high purity by performing the following sequential processes comprising: (i) hydrolysis of lovastatin as starting material with potassium t-butoxide in an organic solvent and small amount of water under a mild reaction condition, followed by lactonization of the obtained solid intermediate with preventing from formation of by-products; (ii) protection of an alcohol group with t-butyldimethylsilyl group which can be easily removed with concentrated hydrochloric acid without the formation of by-products; (iii) acylation of the obtained protected intermediate with acyloxytriphenyl phosphonium salt as an acylating agent under a mild reaction condition; and (iv) removal of the silyl protective group with a concentrated hydrochloric acid. The present invention is to provide the improved process of preparing simvastatin expressed by formula 1 environmentally sound, economically efficient, and industrially useful.

This application is a 371 of PCT/KR01/00301 filed Feb. 27,2001.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to an improved process for preparingsimvastatin and more particularly, the improved process for preparingsimvastatin expressed by formula 1 with high yield and high purity byperforming the following sequential processes comprising:

(i) hydrolysis of lovastatin as starting material with potassiumt-butoxide in an organic solvent and small amount of water under a mildreaction condition, followed by lactonization of the obtained solidintermediate with preventing from formation of by-products;

(ii) protection of an alcohol group with t-butyldimethylsilyl groupwhich can be easily removed with concentrated hydrochloric acid withoutthe formation of by-products;

(iii) acylation of the obtained protected intermediate withacyloxytriphenyl phosphonium salt as an acylating agent under a mildreaction condition; and

(iv) removal of the silyl protective group with a concentratedhydrochloric acid.

The present invention is to provide the improved process of preparingsimvastatin expressed by formula 1 environmentally sound, economicallyefficient, and industrially useful.

Simvastatin of formula 1 is known as antihypercholesterolemic agent thathas excellent inhibitory activity of the HMG-Co A reductase and itspreparing methods have been also intensively studied. General processesof preparing simvastatin of formula 1 include hydrolysis of lovastatin,lactonization, protection of an alcohol in lactone ring, acylation, anddeprotection. Many patents are published with improved process forpreparing simvastatin by characterizing each step of the process.Especially, purity of the product varies with the final deprotectionstep of the process.

When t-butyldimethylsily group is introduced as a protecting group toobtain the compound of formula 2, the deprotection reaction suffers frompoor conversion to simvastatin due to formation of by-products such ascompounds of formula 3 and formula 4.

These by-products of the compounds 3 and 4 cannot be easily removed byconventional purifications and thus it affects yield and purity of thefinal product, simvastatin. Use of t-butylammonium fluoride (TBAF) orhydrogen fluoride (HF) having fluoro anion (F⁻) in the deprotection oft-butyldimethylsily group in lactone ring have been reported [J. Org.Chem. 1991, 56, 4929-4932]. However, as shown in scheme 1, theby-product of formula 3 can be generated during prolonged reaction dueto a reaction between a fluoro ion (F⁻) and an acidic α-proton of thecompound of formula 2. Yield of said deprotection with TBAF is 72% [J.Org. Chem. 1991, 56, 4929-4932].

U.S. Pat. No. 4,845,237 and Korean Patent No. 133,599 disclose that0.4-0.8% of the compounds 3 and 4 as by-products are produced during thereaction, resulting decrease in purity.

Another process for preparing simvastatin of formula 1 introducesring-opening of lactone ring to amide group in order to solve theproblem for the formation of by-products as shown in scheme 2 [J. Org.Chem. 1991, 56, 4929-4932].

However, this process also have drawbacks: (i) in order to introduce amethyl group on α-position of substituted butylester group in thecompound of formula 5, an unstable strong base such as a compound offormula 6, which is not appropriate in industrial scale, has to be used;(ii) a by-product such as a dehydrated unsaturated acid of the compound9 which is precursor of the compound of formula 3 is produced during thehydrolysis of the compound of formula 7 and the following acidificationwith hydrochloric acid; (iii) since a high temperature is required toobtain the desired compound of formula 1 from the compound of formula 8,a dimer of the compound of formula 4 is produced as a by-product.

As described above, many processes still produce by-products such as thecompound of formula 3 and the dimer compound of formula 4 and further,these by-products are not easily removed with conventionalpurifications, resulting low purity of simvastatin of formula 1.

In comparison of conventional removals of a protecting group, theprocess of scheme 1 is preferable in industrial scale to preparesimvastatin, but it requires improved method promising high yield andhigh purity without the formation of the by-products of the compounds 3and 4.

And also, there are series of patents to prepare simvastatin of formula1 from lovastatin as the starting material, it still requiresimprovement in hydrolysis and acylation.

SUMMARY OF THE INVENTION

As a result of that the inventors have long been engaged in themanufacture of simvastatin and have conducted intensive studies toresolve the drawbacks, the inventors have noted that introduction oft-butyldimethylsilyl(TBDMS) group as an alcohol protection group andconstruction of deprotection reaction condition not to produceby-products of the compounds 3 and 4 promise highly pure production ofsimvastatin of formula 1 in high yield.

The present invention is also characterized by the process for preparingfrom lovastatin to simvastatin, wherein the process is performed undermild condition and by using reagents which are easy handle andindustrially useful.

Therefore, an object of the present invention is to provide aneconomical and efficient process for preparing simvastatin of formula 1which is useful as the antihypercholesterolemic agent in industrialscale.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is characterized by preparing simvastatin offormular 1 by deprotecting t-butydimethylsilyl protected intermediate offormular 2 with concentrated hydrochloric acid in one or mixed solventselected from the group consisting of tetrahydrofuran, 1,3-dioxane,1,4-dioxane, methoxyethane and diethyl ether.

The present invention is described in more detail hereunder.

The present invention provides the process for preparing simvastatin offormula 1 through the deprotection using a concentrated hydrochloricacid in a selected solvent and the following crystallization of theobtained simvastatin is performed to produce high yield(92%) and highpurity (99.5%; area ratio of HPLC) of the final product.

The deprotection of the present invention is carried in such a mannerthat the concentrated hydrochloric acid is added to a solutioncontaining the compound of formula 2 at −5 to 10° C. for 6 to 7 hrs. Inthe deprotection of the compound of formula 2 to the compound of formula1, there is no formation of by-products.

According to the inventors, yield and purity of simvastatin varies withreaction conditions (i.e., kind of acid, amount of acid, solvent,temperature, reaction time, and the like) in the deprotection of TBDMSprotected intermediate of formula 2.

Examples of the acid are concentrated hydrochloric acid, dilutedhydrochloric acid (diluted concentrated hydrochloric acid with distilledwater), acetic acid, nitric acid, sulfuric acid, hydrofluoric acid,methanesulfonic acid, and p-toluenesulfonic acid. In the use of aceticacid or p-toluenesulfonic acid, the reaction was not occurred at all. Inthe use of nitric acid, sulfuric acid or methanesulfuric acid, thestarting material was disappeared with time but only, by-products whichwere impossible to identify were produced without any formation of theproduct, simvastatin. In the use of hydrofluoric acid or dilutedhydrochloric acid, simvastatin was produced with not enough purityn dueto the formation of by-products of the compounds 3 and 4. On the otherhand, in the use of concentrated hydrochloric acid, simvastatin wasproduced in high purity and high yield without the formation ofby-products. Thus, concentrated hydrochloric acid is the most preferablein the deprotection.

For the preferred reaction conditions, amount of concentratedhydrochloric acid is 5-10% (v/v) to a reaction solvent used, a reactiontime is 6-7 hrs and a temperature is −5-10° C. A reaction solvent is oneor more selected from the group consisting of tetrahydrofuran,1,3-dioxane, 1,4-dioxane, methoxyethane and diethyl ether. A preferredsolvent is a mixture of tetrahydrofuran and 1,4-dioxane (mixed ratio of0-100:100-0) and more preferred ratio thereof is 95:5.

After the deprotection, the obtained simvastatin is crystallized by thefollowing process: (i) dissolving in ethyl acetate at 40-60° C.; (ii)adding n-hexane; and (iii) cooling to room temperature to givesimvastatin in high purity, (99.5%) and high yield (92%). An expectedreason of obtaining high pure simvastatin in crystallization process isno formation of by-products of the compounds 3 and 4, which arerelatively unstable downy crystals and thus interfere in crystallizationof simvastatin.

Conventional methods in the preparation of simvastatin produceby-products of the compounds 3 and 4 in the deprotection which affectcrystallization and thus, lower the yield and purity of the finalproduct, while that of the present invention does not produceby-products in the deprotection carried with concentrated hydrochloricacid and thus, highly pure simvastatin (99.5%, area ratio of HPLC) isproduced after crystallization in high yield (92%).

The present invention is also characterized by the following sequentialprocess comprising; hydrolysis of lovastatin as the starting material,lactonization, protection of an alcohol on the lactone ring, acylationand deprotection under appropriate reaction conditions to obtainsimvastatin of formula 1.

The manufacturing process of preparing simvastatin from lovastatin asthe starting material is described in scheme 3:

(i) Hydrolysis of lovastatin of formula 10 with potassium t-butoxide,organic solvent and small amount of water at a temperature of from −60to 25° C.;

(ii) Lactonization of the hydrolysed intermediate of formula 11 in anorganic solvent in the presence of an acid catalyst;

(iii) Protection of an alcohol group of the compound of formula 12 tot-butyldimethylsilyl(TBDMS) protected intermediate of formula 13 with asilylating agent in the presence of base;

(iv) Acylation of the compound of formula 13 withacyloxytriphenylphosphonium salt of formula 14 in the presence of baseat a temperature of 0-25° C.; and

(v) Deprotection of the acylated compound of formula 2

wherein X represents a halogen atom.

Hereunder is given the more detailed description of the manufacturingprocess of scheme 3.

In the hydrolysis of the present invention, lovastatin which is knowncompound of formula 10 is reacted with potassium t-butoxide and smallamount of water at a temperature of from −60 to 25° C. for 8 hrs in anorganic solvent to give the compound of formula 11 in high yield (94%).Said organic solvent in the hydrolysis is diethylether, dimethoxyethaneor tetrahydrofuran, preferably tetrahydrofuran. 3-10 equivalents ofpotassium t-butoxide is used to lovastatin of formula 10, preferably 5-8equivalents, most preferably 8 equivalents. Addition of small amount ofwater is important in the hydrolysis because water reacts with potassiumt-butoxide to generate OH⁻ which is required to open ester ring of thecompound of formula 10. If amount of water is too small or too much, thehydrolysis does not proceed completely. Therefore, 2-4 equivalents ofwater to lovastatin of formula 10 is preferred, most preferably 2.2equivalents. Unlike known conventional hydrolysis using LiOH in aqueoussolution, the hydrolysis of the present invention produces the solidcompound of formula 11 and thus, it can be possible to remove completely2-methylbutyric acid which is a by-product. Therefore, the yield can bemaximized with the obtained solid compound of formula 11 in thelactonization by preventing esterification between molecules by2-methylbutyric acid.

The solid compound of formula 11 can be lactonized by known methodsrefluxing in toluene or in the presence of acid catalyst in organicsolvent at room temperature to produce the lactonized compound offormula 12 in high yield (98%). Solvent used in lactonization is one ormore selected from the group consisting of toluene, dichloromethane,ethyl acetate, acetonitrile and diethyl ether. Acid used isp-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid.And then, the lactonized compound of formula 12 can be isolated for thenext reaction or directly used for the next silylation without isolationthereof.

An alcohol group on the lactone ring of the compound 12 can be silylatedwith t-butyldimethylsilyl chloride to obtain the silyl group protectedintermediate of formula 13 in high yield (95%). In order to protect thealcohol group selectively, 1-4 equivalents of t-butyldimethylsilylchloride is used in an organic solvent in the presence of base. The baseused in the protection reaction is imidazole, pyridine, triethylamine ormorpholine and the organic solvent used is acetonitrile,dichloromethane, or chloroform, preferably dichloromethane.

The obtained compound of formula 13 is then acylated withacyloxytriphenylphosphonium salt in an organic solvent and under a mildcondition in the presence of base to produce the compound of formula 2without any formation of by-products in high yield (97%). The organicsolvent used in the acylation is dichloromethane, tetrahydrofuran,diethyl ether, acetonitrile, ethyl acetate or acetone, preferablydichloromethane. The base used is pyridine, triethylamine, imidazole,morpholine or 2,6-lutidine. The reaction is preferred to carry in atemperature of from −30 to room temperature and under anhydrouscondition.

Acyloxytriphenylphosphonium salt of formula 14 used in the acylation isprepared by activating 2,2-dimethylbutyric acid with triphenylphophineand halogenation agent as shown in Scheme 4,

wherein X represents a halogen atom.

N-haloimide is preferred as the halogenation agent in the reaction ofScheme 4 and examples thereof include N-chlorosuccinimideN-iodosuccinimide, N-bromosuccinimide, N-chlorophthalimideN-iodophthalimide, N-bromophthalimide, N-bromoacetamide, and1,3-dibromo-5,5-dimethylhydantoin.

The obtained acylated compound of formula 2 is deprotected andcrystallized to produce the desired compound simvastatin of formula 1 asdescribed above. The deprotection and following crystallization are themost characteristic of the present invention.

When the process for preparing simvastatin from lovastatin is performedas described in the present invention, the total yield is over 80% whichis much higher than that of the conventional processes. On top of that,another characteristic of the present invention is to producesimvastatin having high purity economically.

This invention herein is explained in more detail based on the followingexamples without limitations thereby.

EXAMPLE 1 Preparation of7-[1′,2′,6′,7′,8′,8a′(R)-hexahydro-2′(S),6′(R)-dimethyl-8′(S)-hydroxy-1′(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid

To a mixed solution of 500 ml of tetrahydrofuran and 4.7 ml of watercooled to −30° C., was added 111 g of potassium t-butoxide, following 50g of lovastatin. After the reaction mixture was stirred at roomtemperature for 5 hrs, it was cooled to 0° C. and 200 ml of water wasadded and concentrated. The reaction mixture was acidified to pH 2.0with 6N HCl and stirred for 1 hr in cooled condition. The reactionmixture was filtered, washed with 100 ml of water and 100 ml ofdichloromethane and then dried to obtain 39.3 g (94%) of white solidcompound.

mp 127-128° C.;

IR(KBr) 3453, 3389, 1720, 1649 cm⁻¹;

¹H NMR (DMSO, 400 MHz) δ 0.79(d, J=6.9 Hz, 3H), 1.11(d, J=7.30 Hz, 3H),1.10-2.36(m, 14H), 3.56(brs, 1H), 3.99(brs, 2H), 4.06(brs, 1H),4.42(brs, 1H), 4.70(brs, 1H), 5.37 (brs, 1H), 5.68-5.73(m, 1H), 5.86(d,J=9.60 Hz, 1H), 11.96(brs, 1H).

EXAMPLE 2 Preparation of6(R)-[2-[8′(S)-hydroxy-2′(S),6′(R)-dimethyl-1′,2′,6′,7′,8′,8a′(R)-hexahydronaphthyl-1′(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on

10 g of triolic acid prepared in Exmple 1 was suspended into 100 ml ofdichloromethane and 112 mg of p-toluenesuifonic acid was added andstirred for 1 hr at room temperature to complete lactonization. Thereaction mixture was washed with saturated sodium bicarbonate solution,water and saturated brine and then dried and concentrated to give 9.2 g(97%) of the desired compound.

mp 127-128° C.;

IR(KBr) 3374, 2972, 2912, 1704 cm⁻¹; and

¹H NMR (CDCl₃, 400 MHz) δ 0.89(d, J=7.0 Hz, 3H), 1.18(d, J=7.5 Hz, 3H),1.40-2.75(m, 14H), 4.24(brs, 1H), 4.34-4.38(m, 1H), 4.68-4.73(m, 1H),5.54(brs, 1H), 5.77-5.81(m, 1H), 5.97(d, J=9.60 Hz, 1H)

EXAMPLE 3 Preparation of 6(R)-[2-(8′(S)-hydroxy-2′(S),6′(R)-dimethyl-1′,2′,6′,7′,8′,8′a(R)-hexahydronaphthyl-1′(S))ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-on

9.2 g of the obtained lactonized compound was dissolved in 80 ml ofdichloromethane and 8.0 g of imidazole and 8.9 g of t-butyldimethylsilylchloride were added. The reaction mixture was stirred for 15 hrs at roomtemperature. The reaction mixture was washed with 5% of aqueoushydrochloric acid solution, water and saturated brine and then driedover anhydrous MgSO₄ and concentrated to produce the compound which isadded into 200 ml of hexane and stirred at cooled condition for 1 hr andthen filtered, washed with hexane and dried to give 12.3 g (95%) of thedesired white solid compound.

mp 133-134° C.;

IR(KBr) 3483, 1712 cm⁻¹; and

¹H NMR (CDCl₃, 400 MHz) δ 0.06(s, 3H), 0.07(s, 3H), 0.88(s, 9H), 0.89(d,J=7.22 Hz, 3H), 1.18(d, J=7.51 Hz, 3H), 1.48-2.60(m, 14H), 4.24(brs,1H), 4.28-4.30(m, 1H), 4.66-4.69(m, 1H), 5.54(brs, 1H), 5.77-5.82(m,1H), 5.97(d, J=9.64 Hz, 1H).

EXAMPLE 4 Preparation of6(R)-[2-(8′(S)-2″,2″-dimethylbutyryloxy-2′(S),6′(R)-dimethyl-1′,2′,6′,7′,8′,8′a(R)-hexahdronaphthyl-1′(S)ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on

5.34 g of 2,2-dimethylbutyric acid was dissolved in 100 ml ofdichloromethane and 13.3 g of triphenylphosphine was added and cooled to0° C. After adding 8.6 g of N-bromosuccinimide, the reaction mixture wasstirred for 30 min at room temperature to produceacyloxytriphenylphosphonium salt. After cooling the reaction mixture to0° C., 5 g of the obtained compound prepared in Example 3 and 6.2 ml ofN,N-dimethylaniline were added. The temperature was increased to roomtemperature and then the reaction mixture was stirred for 10 hrs at roomtemperature. The reaction mixture was washed with 5% of aqueoushydrochloric acid solution, water, saturated sodium bicarbonatesolution, water and saturated brine and then concentrated to give cakewhich was added to 100 ml of hexane and stirred for 30 min at 0° C. Thereaction mixture was filtered and the filtrate was concentrated toproduce 6.0 g (97%) of the acylated oily compound. The compound was usedfor next reaction without further purification due to its high purity.

The acylated compound was dissolved in 48 ml of tetrahydrofuran and 2.5ml of 1,4-dioxane. After the mixture was cooled to 0° C., 3.5 ml ofconcentrated hydrochloric acid was added and stirred for 6 hrs tocomplete the reaction. Triethylamine was added to adjust pH to 1.5 andthen concentrated to dryness. And then 40 ml of ethyl acetate was addedand washed with water and saturated brine. The ethyl acetate layer wasdried over MgSO₄ and concentrated to give colorless cake. The cake wasdissolved in 35 ml of dichloromethane and 0.07 g of p-toluenesulfonicacid was added and stirred for 1 hr at room temperature. The reactionmixture was concentrated and 15 ml of ethyl acetate was added and heatedto 40-60° C. 60 ml of n-hexane was added slowly and then cooled to roomtemperature. After the reaction mixture was stirred for 1 hr, it wascooled to 0° C. and stirred again for 2 hrs to produce white precipitatewhich was filtered and dried. The obtained white solid was dissolved in50 ml of methanol and small amount of activate carbon was added andstirred for 30 min. The activate carbon was removed by filteration and50 ml of water was added to the filtrate and the mixture was cooled to0° C. and stirred for 2 hrs to produce white precipitate. Theprecipitate was collected through filtration and dried under the vacuumto give 4.4 g (92%) simvastatin with high purity (over 99.5%, area ratioof HPLC).

mp 134-136° C.;

IR(KBr) 3552, 1730-1698 cm⁻¹; and

¹H NMR (CDCl₃, 400 MHz) δ 0.83(t, J=7.5 Hz, 3H), 0.88(d, J=7.0 Hz, 3H),1.08(d, J=7.4 Hz, 3H), 1.12(s, 3H), 1.13(s, 3H), 1.20-1.96(m, 10H),2.28-2.76(m, 6H), 4.37(m, 1H), 4.60(m, 1H), 5.36(m, 1H), 5.51(bt, J=3.3Hz, 1H), 5.77(dd, J=6.1, 9.6 Hz, 1H), 5.98(d, J=9.6 Hz 1H).

Deprotection and crystallization reactions were performed with variousacids as the same procedure of Example 4 and the results are shown inTable 1.

TABLE 1 Result Category Yield Purity¹⁾ crystallity²⁾ By-products Conc.92% 99.5% 5   Below 0.3% Hydrochloric acid Acetic acid (75%) — — — Noreaction p-toluenesulfonic — — — No reaction acid (95%) HF (50%) 56-67%82-86% 3   More than 10% (more than 50 hr reaction) TBAF 60-65% 85-92%3.5 1.6-15% (more than 26 hr reaction) Nitric acid — — — No starting(20-50%) material and no product Sulfuric aicd — — — No starting(20-50%) material and no product Methanesulfonic — — — No starting acid(20-50%) material and no product Diluted 40-60% Higher 3   More than 15%hydrochloric acid than 85% (more than 50 hr (6N—HCl) reaction) ¹⁾purityarea ratio of HPLC ²⁾crystallity: 5 (good)1 (bad)

Deprotection and crystallization reactions were performed with variousorganic solvents as the same procedure of Example 4 and the results areshown in Table 2.

TABLE 2 Result Category Yield Purity¹⁾ Crystallity²⁾ By-productsTetrahydrofuran/ 92% 99.5% 5 Less than 0.3% 1,4-dioxane (6-7 hrs of(95/5, V/V) reaction time) Methoxy ethane 50% Over 70% 3 Less than 5%(more than 10 hrs of reaction time) Tetrahydrofuran Over 90% Over 92% 5Less than 2% (3-4 hrs of reaction time) 1,4-dioxane Over 80% Over 85%3.5 Less than 3% (more than 10 hrs of reaction time) 1,3-dioxane Over80% Over 90% 4 Less than 5% (more than 10 hrs of reaction time)¹⁾Purity: area ratio of HPLC ²⁾Crystallity: 5 (good)1 (bad)

The superiority of the present invention is showing in the Examples andfurther detailed description is followed hereunder.

First, in deprotection of the TBDMS protected intermediate of formula 2,conventional method is performed with tetrabutylammoniumfluoride(TBAF)/acetic acid or HF for a long period (over 18 hrs) but itproduces semi-pure-product in low yield (72%, overall yield of 48%) dueto the formation of by-products such as the compounds of formulas 3 and4. On the other hand, it is performed in a particular solvent such astetrahydrofuran or 1,4-dioxane for much shorter time of 6-7 hrs toproduce simvastatin without the formation of such by-products of thecompounds 3 and 4 in high purity (over 99.5%) and high yield (92%).

Second, in the hydrolysis to produce the compound of formula 11,conventional method is performed for 56 hrs under a vigorous conditionso that it produces irresistible by-products and further removal of2-methylbutyric acid, which is another product during the reaction, isnot possible because the hydrolyzed product is an oil. And thus, this2-methylbutyric acid participates in esterification reactions betweenmolecules so that the yield of this reaction cannot be higher than 81%.On the other hand, the hydrolysis of the present invention is performedfor much shorter time of 8 hrs at a temperature of from −60 to 25° C.with minimizing the formation of by-products and further, the compoundof formula 11 can be obtained in a solid state without containing2-methylbutyric acid, resulting in no side reactions. Thus, the compoundof formula 11 can be obtained in high yield of 94% in the hydrolysis ofthe present invention and the overall yield of preparing the compound offormula 12 is 92%.

Third, a typical solvent in the conventional protection reaction of analcohol group is N,N-dimethylformaldehyde which is difficult to removeafter the reaction so that the yield is around 69%, while the presentinvention uses an organic solvent which is easy to remove, resultinghigh yield of over 95%.

Fourth, the acylation of the conventional method requires the formationof acid chloride salt and have environmental problems such as theformation of sulfur dioxide and hydrochloric acid gas due to the use ofthionyl cloride to produce acid chloride salt. However, that of thepresent invention is simply performed byt using very reactiveacyloxyltriphenylphosphonium salt of formula 14 without producing acidchlorides. On top of that, it is profitable in industrial scale forperforming the reaction in dichloromethane at a temperature of 0-25° C.in the present invention in stead of using poisonous pyridine at a hightemperature of 100° C. in the conventional method. The overall yield ofacylation and deprotection of the compound of formula 13 is 76% in theconventional method, while over 90% to produce the compound of formula 1in the present invention.

As a result, the overall yield from lovastatin of formula 2 tosimvastatin of formula 1 is 48% by the conventional process while over80% by the present invention.

Therefore, the present invention is expected to provide the improvedprocess of preparing simvastatin expressed by formula 1 which isefficient in the treatment of hyperlipemia in an industrial scale.

What is claimed is:
 1. A process for preparing simvastatin of formula 1by deprotecting t-butyldimethylsilyl protected intermediate of formula 2with concentrated hydrochloric acid in one or mixed solvent selectedfrom the group consisting of tetrahydrofuran, 1,3-dioxane, 1,4-dioxane,methoxyethane and diethyl ether


2. The process for preparing simvastatin according to claim 1, whereinsaid solvent is a mixture of tetrahydrofuran and 1,4-dioxane.
 3. Theprocess for preparing simvastatin according to claim 1, wherein saidobtained deprotected compound is further crystallized by dissolving inethyl acetate at 40-60° C. and adding n-hexane thereto.
 4. The processfor preparing simvastatin according to claim 1, wherein said protectedcompound of formula 2 is prepared by the following processes comprising:(i) hydrolyzing lovastatin of formula 10 with potassium t-butoxide in anorganic solvent and small amount of water at from −60 to 25° C. andfurther lactonizeing the hydrolyzed compound in an organic solvent inthe presence of acid to produce the compound of formula 12; (ii)protecting the alcohol group of the compound of formula 12 witht-butyldimethylsilyl group in the presence of base to produce thecompound of formula 13; and (iii) acylating the compound of formula 13with acyloxytriphenyl phophonium salt of formula 14 in the presence ofbase at a temperature of 0-25° C. to produce the compound of formula 2,

wherein X represents a halogen atom.
 5. The process for preparingsimvastatin according to claim 4, wherein said (i) hydrolysis isperformed with potassium t-butoxide and 2-4 equivalents of water intetrahydrofuran or diethyl ether.
 6. The process for preparingsimvastatin according to claim 4, wherein said (ii) protection isperformed in dichloromethane.
 7. The process for preparing simvastatinaccording to claim 4, wherein said acyloxytriphenylphosphonium salt in(iii) acylation is prepared by reacting 2,2-dimethylbutyric acid withtriphenylphosphine and a halogenating agent.
 8. The process forpreparing simvastatin according to claim 7, wherein said halogenatingagent is selected from the group consisting of N-bromoacetamide,N-bromosuccinimide, N-chlorosuccinimide, N-bromophthalimide,N-chlorophthalimide and 1,3-dibromo-5,5-dimethylhydantoin.
 9. Theprocess for preparing simvastatin according to claim 4, wherein said(iii) acylation is performed in an organic solvent selected from thegroup consisting of dichloromethane, tetrahydrofuran, toluene, andacetone.